Pharmaceutical Aerosols A System that depends on the power of a compressed

or liquefied gas to expel the contents from thecontainer.

1942- Goodhue & Sullivan.

1950- Topical Pharmaceutical Aerosol.

1955- Epinephrine aerosol for local action.

Aerosol products containing therapeutically activeingredients dissolved, suspended or emulsified in apropellant or a mixture of solvent and propellant andintended for topical administration, administration into body cavities, or for administration orally ornasally as fine solid particles or liquid mists throughpulmonary airways, nasal passage or oral cavity.

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Advantages of Aerosol dosage forms.

a. Ease & convenience for application.

b. Dose is administered with outcontaminating remaining product.

c. Stability is enhanced for materials affectedby oxygen or moisture.

d. Sterility of the product is maintained whendose is administered.

e. The medication is delivered directly to theaffected area in the desired foam.

f. Irritation caused by mechanical applicationor topical medication can be reduced oreliminated.

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g. Rapid onset of action.

h. Avoid degradation of drug at GIT or

through first pass effect.

i. Lower dose of drug can be used which

minimizes possible adverse effects.

j. Application of medication as thin layer or

film.

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Components of Aerosol Package.

1. Propellant.

2. Container.

3. Valve and actuator.

4. Product concentrate.

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1. Propellant• Helps in Atomization or foam product.Fluorinated hydrocarbons Oral & Inhalation use

Trichloromonofluoromethane (Propellant 11)Dichlorodifluoromethane (Propellant 12)Dichlorotetrafluoroethane (Propellant 114)

Hydrocarbons Topical pharmaceutical aerosols.

Propane, Butane, Isobutane etc.Compressed gas Topical pharmaceutical aerosols.

Nitrogen, Carbon dioxide, Nitrous oxide etc.

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• Blends of propellants are preferred.

• With in limits of individual propellant vapor

pressure.

• Purity effects vapor pressure of propellant.

Daltons law

Total pressure of any system is equal to the

sum of the individual or partial pressure of

the various components.

P = pa + pb

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pa na pAo NA pA

o

na + nb

pa = Partial vapor pressure of propellant A

pAo = Vapor pressure of pure propellant A

na = Moles of propellant A

NA = Mole fraction of component A

pb nb pBo NB pB

o

nb + na

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Liquefied gas Vs Compressed gas

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2. Containers◦ 140-180 Psig at 130o F

A. Metal

1. Tin plated Steel

Side seam (Three piece)

Two piece or drawn

Tin Free Steel

2. Aluminum

Two piece

One piece (Extruded or drawn)

3. Stainless steel

B. Glass

1. Uncoated glass

2. Plastic coated glass

C. Plastic

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1. Tin plated containers

Electroplated on both side by tin.

Thickness in terms of weight: # 25, # 50, # 100.

Size indicated by diameter x height.

22/16 x 214/16 or 202x214)

Tin plated steel are obtained as thin sheet and

may be coated with organic materials.

Body-Top-Bottom.

Flanging- Soldering- Welding.

Coating on finished container is efficient & defect

free but time consuming.

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2. Aluminum containers

Lesser incompatibility & corrosion free.

Ethanol-Propellant 11 produce hydrogen, acetylchloride, aluminum chloride, propellant 21 & othercorrosive products.

6Al + 6C2H5OH(Anhydrous) 2(C2H5O)3 Al + 3H2

3. Stainless steel containers

• Stronger, resistance to corrosion.

No organic coating needed.

Inhalation aerosols.

Limited usage, cost, production problems.

4. Glass containers

With or with out plastic coating.

Greater design options

No incompatibility & Its use is limited for productshaving lower pressure and lower percentage ofpropellant.

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Why curved bottom???

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1-The shape strengthens the structure of the

can.

A curved bottom has greater structural integrity.

2-The shape makes it easier to use up all the

product.

Valves

Multifunctional & USFDA approved.

Consists of different parts,

Ferrule or Mounting cup

Valve body or Housing

Stem

Gasket

Spring

Dip tube

Metering valves

Actuators

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1. Ferrule or Mounting cup

Attach the valve assembly to the container.

Made up of tin platted steel or aluminum.

Ferrule for glass bottle or small aluminum

tubes are made up of softer aluminum or

brass.

Underside of valve cup is coated with epoxy

or vinyl coating.

Attached to container by rolling the end

under the lip of the bottle or clinching the

metal under the bottle lip.aerosol- scs

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2. Valve body or Housing

Nylon or Delrin.

Opening at the area of attachment with dip tube ( 0.013-0.080 inches).

Vapor tap allows the escape of vaporisedpropellant along with liquid product.

Vapor tap produces finer particles, preventsclogging of insoluble materials& allowssatisfactory removal of product fromcontainer.

Vapor tap avoids chilling effect and reduceflame extension in case of HC propellants.

Vapor tap ranges between 0.013-0.080inches.aerosol- scs

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3. Stem

Nylon,Delrin,Stainless steel or Brass.

One or more orifice ranging between 0.013-

0.030 inches. (Three orifice of 0.040 inches

each).

4. Gasket

Buna-N & Neoprene rubber.

Compatible with formulations.

5. Spring

Stainless steel.

Holds the gasket in place.

Helps the functioning of valve assembly.aerosol- scs17

6. Dip tube

Polyethylene or Polypropylene (Rigid).

Viscosity & delivery rates plays the role in

selection.

Inside diameter 0.120-0.125 inches.

0.050 inches capillary tubes & 0.195 inches

wider tubes available.

7. Metering valves

Potent medication.

Chamber size fixes the medication.

Limitations of size& dosage accuracy.

50- 150 mg ±10% liquid materials dispensed at

one time.aerosol- scs18

8. Actuator

Ensure delivery in proper & desired form.

Easy opening & closing of valve assembly.

Different types of Actuators

◦ Spray actuator

◦ Foam actuator

◦ Solid stream actuator

◦ Special applications

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a) Spray actuator• Disperse stream of product concentrate &

propellant in to smaller particles by passingthrough various openings (0.016-0.040 inches).

• Large % of propellant mixture with sufficientquantity of low boiling propellant (propellant 12 orpropane) large orifice actuators used.

• Combination of propellant vaporization, actuatororifice & internal channels may deliver spray indesired particle size.

• Used as topical sprays ie., bandages, antiseptics,local anesthetics & foot care preparations.

• Products with low % of propellants (50% or<),dispersed as stream than a spray. Mechanicalbreak up actuators as used in this case.

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b) Foam actuator

Large orifice (0.070-0.125 inches or >)

Product reaches in large chamber thenexpand before dispensed through theorifice.

c) Solid stream actuator

Semi-solid products.

Similar to Foam type actuators.

d) Special actuator

Used for special purposes.

To deliver into throat, nose,eye & vaginaltract.

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Metered Dose Inhalers (MDI) Modifications made to reduce existing errors.

Tube spacers, Breath actuator, Portable plasticreservoirs & Propellant free metered pumps.

Deliver drug at Nasal, Intra-nasal pathways&Respiratory pathways.

Deliver only 10-15% actuated dose of drug.

10% lost at inner surface of adaptor.

80% inertial impact/deposit at oropharynx.

Altered geometry/ shape/size tube spacers usedto reduce the 80% fraction loss.

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Tobin et. al, Reservoir Aerosol Delivery System(RADS).Consists of 700 ml capacity collapsible plastic bag in towhich aerosol is injected.(InspireEase by KeyPharmaceutical Inc).

Provided with special mouth piece.

Warning alarm beep system.

Propellant free intra-nasal pump- Flunisolide-Seasonal& allergic rhinitis.

Reduce irritation & smarting at nasal mucosa.

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Metered Dose Inhaler

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Formulation of Pharmaceutical Aerosol

Product concentrate & Propellant.

AI, Solvents,Antioxidents,Surfactants.

Propellants for desired vapor pressure.

Factors for selection of systems

Physical,Chemical,Pharmacological

properties of AI.

Site of application.

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Solution system Two phase system (V&L).

No solvent required when AI is soluble inPropellant.

Propellant-12/A-70 or mixture of propellant-12.

Lower vapor pressure than propellant-12 produceslarger particles.

Low volatile solvents: Ethyl alcohol, Acetone,Propylene glycol, Ethyl acetate, Glycerin canproduce low VP.

5%- Foam type--------------------95%- Inhalation type.

Larger particle size sprays used as topicalformulations.

System avoids inhalation of airborne particles.

Chilling effect: Depending up on BP of solventused, rate of vaporization of propellant may be

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Active Ingredients : 10-15%

Propellant 12/11 : up to 100%

For oral inhalation aerosols, FDA exempted contraceptives.

Propellant 12/11 (30:70)

Propellant 12/114 (45:55)/ (55:45)

Aerosol (Inhalation type): 15-30ml SS/Al/Glass containers

Isoproterenol HCl : 0.25%

Ascorbic Acid : 0.10%

Ethanol : 35.75%

Propellant-12 : 63.90%

Aersol (Inhalation type): Reduced vapor pressure

Octyl Nitrite : 0.1%

Ethanol : 20.0%

Propellant-114 : 49.2%

Propellant- 12 : 30.7%

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System with Hydrocarbon Propellant

Depending up on water content final product may become

solution or three phase system. Concentration of ingredients

may produce finer to coarser spray.

Propellant A-70: Dry spray.

Propellant A-17 & A-31: Wet spray.

System can be packed in plastic coated glass container.

Propellant content shall not exceed 15% of total product

weight.

Volumetric capacity shall not exceed 5 fl.oz.

Topical formulation with hydrocarbon propellant

Active Ingredients : 10-15%

Solvent : 10-15%

Distilled water : 10-15%

Hydrocarbon propellant, A-46 : 55-70%aerosol- scs29

Testing of products made from hydrocarbon

propellants

1/1000: Test at 250 psig with out failure.

1/20000: Bursting point & Bursting pressure (not

less than 300psig).

1/20000: Dropped from 4 ft with out flying glass &

Shattering effect.

10 additional bottles tested for each failed test.

Further failure forces rejection of whole batch.

1/1000: Heated so that pressure with in the

container is equivalent to equilibrium pressure of

contents at130o F with out evidence of any

leakage or defect.

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Water based system

Non-aqueous solvents are replaced in full or partial.

Propellant 25-60% (low as 5%)

Formulation emitted as spray or foam.

Spray: Dispersion of active ingredients & solvents asemulsion with propellant as external phase. Leaves activeingredients as minute particles.

Propellant phase ≠ Water phase- Vapor phase.

Ethanol (co-solvent) to solubilise some of the propellant inwater & reduce particle size.

Surfactants: Produce homogenous dispersion. Low watersolubility & High solubility in non-polar solvents. Eg: Longchain fatty acid esters of poly hydroxylic compoundsincluding glycol, glycerol, sorbitol esters of oleic, stearic,palmitic &lauric acid. (0.5- 2.0%)

Mechanical break up/vapor tap actuators.

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Aquasol system

Three phase system, contains large quantity of water.

Aquasol valve.

Dispensing of a fine mist or spray of active ingredient

dissolved in water. No chilling effect experienced as with

normal hydrocarbon propellant system.

Need low concentration of propellant but effectively &

economically disperse the product.

Fluorocarbon propellants can be used.

Dispense dry spray with fine particles in comparison with

three phase system. Aquasol valve dispense vaporized

propellant than liquefied propellant.

Non-flamable stream of product dispersed.

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Active ingredients dissolved or suspended in water ormixture of alcohol & water.

Hydrocarbon propellant floats on top of aqueous layer &exists as both liquid & vapor.

Depending up alcohol concentration propellant-water/alcohol layer may or may not be immiscible.Miscibility improves with increase in alcohol concentration.

As pure alcohol system is approached, complete miscibilitytakes place. System becomes two phase system.

Flammability increases with two phase system. Liquidpropellant is dispensed.

Vapor phase of propellant and product concentrate entersthe actuator through separate channels at high velocitycausing mixing of vapor and product resulting in finelydispersed spray.

Fine dry spray & coarse wet spray depending up on valve& actuator.

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Suspension or Dispersion systems

Mainly as oral inhalations.

Overcome the difficulties caused due to co-solvents.

Dispersion of active ingredients in the propellant/mixture.

Reduce settling by using surfactants or suspending agents.

Methods to improve physical stability of aerosol dispersions

Control moisture content (< 300ppm)

Derivatives with minimum propellant solubility.

Reduction of initial particle size < 5µm.

Density adjustment between propellant and/or suspensoid.

Dispersing agents.

Vapor tap valves reduces valve clogging complaints.

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Active ingredient with minimum solubility in propellantsystem.

Epinephrine bitartrate : 0.50%

Sorbitan trioleate : 0.50%

Propellant 114 : 49.50%

Propellant 12 : 49.50%

Formulation with dispersing agent /lubricant to preventaggregation.

Steroid compound : 8.4 mg

Oleic acid : 0.8 mg

Propellant 11 : 4.7 gm

Propellant 12 : 12.2 gm

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Foam systems

Stable or quick breaking foams.

Emulsion or foam aerosol: Active ingredients, aqueous or non

aqueous vehicle, surfactant & propellant.

Liquefied propellant is emulsified and used as internal phase.

Steroids, antibiotics are dispensed using hydrocarbon or

compressed gas propellants.

Fluorocarbons are banned except for contraceptives.

Aqueous stable foams

Active ingredients

Oil waxes

o/w surfactant : 95.0- 96.5%

Water

Hydrocarbon propellant : 3.5-5.0%

Lower propellant yields wetter foam.

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Nonaqueous stable foams

Use various glycols: PEG (91.0-92.5%)

Emulsifiers from the class of Glycol esters, Eg: Propylene glycolmonostearate. (4.0%)

Hydrocarbon propellants (3.5-5.0%)

Quick-Breaking foam

Propellant is the external phase.

Product dispensed as a foam then break down in to liquid.

Topical application.

Surfactant can be non-ionic, cationic or anionic but soluble inalcohol and water.

90% AI & 10% Propellant packaged at pressure below 25 psig.

Ethyl alcohol : 46.0- 66.0%

Surfactant : 0.5-5.0%

Water : 28.0-42.0%

Hydrocarbon propellant : 3.0-15.0%

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Thermal foams

Warm shaving foams.

Dispense hair dyes/colous.

Inconvenience to use,expense,corrosion.

May be useful in medicated aerosol due to heat.

Intranasal aerosols.

Delivery of measured dose,

Depth of penetration.

Minimal inadvertent penetration to lungs.

Reduced droplet or particle size.

Lower dosage than comparable systemic preparation.

Sterility maintained dose to dose.

Greater patient compliance.

Decreased mucosal irritation.

Greater flexibility in formulation.

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Basic formulation of intranasal aerosol

Active ingredients (Micronised) : up to 1.0%

Dispensing agent, additives, solvents etc : up to 1.0%

Propellant 12/11 (60:40) : up to 98.0%

Decadron Turbinaire: Dexamethasone sodium phosphate-

Allergic or inflammatory nasal conditions.

Beconase Vancenase: Beclomethasone dipropionate-

Seasonal and perennial rhinitis.

Major difference from inhalation aerosol is the design of

adaptor which is considerably shorter & narrower

minimizing propellant vaporization before contacting nasal

mucosa.

This results in desirable lower percentage of smaller

particles which reduces number of particles entering in to

respiratory airways.

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Manufacture of Pharmaceutical Aerosols

Special knowledge, Skills and equipment-low temperature (-

40o F).

Pressure Filling Apparatus

Pressure burette fills small volume of liquefied gas under

pressure in to an aerosol containers.

Propellant is introduced through in-let valve located either at

bottom or top of the burette. Trapped air is allowed to

escape.

Propellant is allowed to flow through the aerosol valve in to

the container under its own vapor pressure. Filling is

stopped when pressure becomes equal.

To fill additional propellant, a hose leading to a cylinder of N2

or compressed air is attached to the upper valve causing

propellent to flow.

Piston type filling apparatus is used but can not fill through

metered valve.(Pressure- fillable metered valves areaerosol- scs

41

Cold Filling Apparatus

Similar to pressure filling apparatus.

Coiled copper tube placed inside the insulated box filled with

dry ice/acetone.

May be used for metered and non-metered valves.

Should not be used for hydrocarbon propellant systems

since excessive escaping of vapor may form explosive

mixture at floor level.

Heavier fluorocarbon do not form such mixtures.

Restricted to non-aqueous products and those products

which are not adversely affected by low temperature.

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Compressed Gas Filling Apparatus

Compressed gases are under high pressure, pressurereducing valve is required.

Flexible hose (150pounds/sq. inch) is fitted with filling head.

Product concentrate is placed in the container and crimpedwith valve.

Filling head is attached to valve opening.

Depression of valve allow the compressed gas to enter thecontainer.

Pressure with in the container becomes equal to deliverypressure, filling stops.

For those products which needs higher amount of gas orsolubility of gas in product concentrate,CO2 or Nitrous oxidecan be used.

Maximize the solubility of gas in product, manual ormechanical shaking can be done during & after the filling.

aerosol- scs43

Large scale equipment

GMP in filling process.

Concentrate Filler

Single-stage single hopper to large straight line multiplehead filler or rotary type multiple head filler.

Constant rate filling will be done in 1-2 operations.

Valve Placer

Manually or automatically prior to crimping.

High speed automatic valve placers.

Purger & Vacuum crimper

Operate manually or by air pressure (80 pound/sq.inch)crimping 10-12 cans/minute.

Dual function: evacuation of air to about 24 inches ofmercury and seal the valve.

Multiple head rotary unit capable of vacuum crimping up to120 cans/ minute.

aerosol- scs44

Pressure Filler

Adding propellant through valve assembly before crimping.

Positive pressure is used.

Single/Multiple stage process.

Under cap filling:- A seal is made by lowering crimping bell on tothe container.

Air is removed by vacuum, propellant is metered in to container.

Crimps the valve to the container.

Leak Test Tank

Large tank filled with water, heating units and magnetized chain.

Length of the tank is such that the temperature of productbefore it emerges from tank is 130o F.

DOT: “each completed container filled for shipment must havebeen heated until contents reached a minimum of 130o F, orattained the pressure it would exert at this temperature with outthe evidence of leaking, distortion or other defects”

aerosol- scs45

Fully automatic filling process

aerosol- scs46

Testing of Pharmaceutical aerosols.

Flame Projection

This test indicates the effect of an aerosol formulation on the

extension of an open flame.

Product is sprayed for 4 sec. into flame.

Depending on the nature of formulation, the fame is

extended, and exact length was measured with ruler.

Flash point

Determined by using standard Tag Open Cap Apparatus.

Aerosol product is chilled to temperature of -25º F and

transferred to the test apparatus.

Temperature of test liquid increased slowly, and the

temperature at which the vapors ignite is taken a flash point.

Calculated for flammable component, e.g. topical

hydrocarbons.aerosol- scs

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Vapor pressure

Determined by pressure gauge

Variation in pressure indicates the presence of air in headspace.

Density

Determined by hydrometer or a pychnometer.

Moisture content

By Karl Fischer method / gas chromatography.

Identification of propellants

I.R spectrophotometry

Aerosol valve discharge rate

Determined by taking an aerosol known weight anddischarging the contents for given time using standardapparatus.

By reweighing the container after time limit has expired, thechange in weight per time dispensed is discharge rate ingram per seconds.aerosol- scs

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Dose uniformity

To determine amount of medication actually received by thepatient.

The method involves accurate weighing of filled containerfollowed by dispersing of several doses.

Container can reweighed.

Difference in weight divided by no of dose give the averagedose.

Net contents

Weight filled full container.

Dispensing the contents, then reweight the container.

The difference in weight, will be the net weight.

Leakage

Used to estimate the weight loss over a 1-year period.

aerosol- scs49

Foam stability

Visual evaluation, time for given mass to penetrate the

foam, time for given rod inserted in to foam and to fall&

using rotational viscometers.

Particle size determination

Cascade impactor & light scatter decay.

Stream of particles projected through series of nozzle&

glass slides at high velocity.

Larger particles impacted first at low velocity and smaller

pass on and collected high velocity.

Specific for aerosol containing particles targeted for RT.

Biological testing/Therapeutic activity/ Toxicity

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